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Current Analytical Chemistry

Editor-in-Chief

ISSN (Print): 1573-4110
ISSN (Online): 1875-6727

Review Article

Reactive Metabolites: Generation and Estimation with Electrochemistry Based Analytical Strategy as an Emerging Screening Tool

Author(s): Maria Bandookwala, Kavya Sri Nemani, Bappaditya Chatterjee and Pinaki Sengupta*

Volume 16, Issue 7, 2020

Page: [811 - 825] Pages: 15

DOI: 10.2174/1573411016666200131154202

Price: $65

Abstract

Background: Analytical scientists have constantly been in search for more efficient and economical methods for drug simulation studies. Owing to great progress in this field, there are various techniques available nowadays that mimic drug metabolism in the hepatic microenvironment. The conventional in vitro and in vivo studies pose inherent methodological drawbacks due to which alternative analytical approaches are devised for different drug metabolism experiments.

Methods: Electrochemistry has gained attention due to its benefits over conventional metabolism studies. Because of the protein binding nature of reactive metabolites, it is difficult to identify them directly after formation, although the use of trapping agents aids in their successful identification. Furthermore, various scientific reports confirmed the successful simulation of drug metabolism studies by electrochemical cells. Electrochemical cells coupled with chromatography and mass spectrometry made it easy for direct detection of reactive metabolites. In this review, an insight into the application of electrochemical techniques for metabolism simulation studies has been provided. The sole use of electrochemical cells, as well as their setups on coupling to liquid chromatography and mass spectrometry has been discussed. The importance of metabolism prediction in early drug discovery and development stages along with a brief overview of other conventional methods has also been highlighted.

Conclusion: To the best of our knowledge, this is the first article to review the electrochemistry based strategy for the analysis of reactive metabolites. The outcome of this ‘first of its kind’ review will significantly help the researchers in the application of electrochemistry based bioanalysis for metabolite detection.

Keywords: Bioactivation, conventional techniques, electrochemical analysis, mass spectrometry, reactive metabolite generation, reactive metabolite.

Graphical Abstract

[1]
Guidance for industry. Safety testing of drug metabolites; Center for Drug Evaluation and Research: Rockville, MD, USA, 2008.
[2]
Guidance for industry. Nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals., 2010.
[3]
Questions and answers (R2) on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. 2013.
[4]
Zhang, D.; Zhu, M.; Humphreys, W.G. Drug metabolism in drug design and development: Basic concepts and practice; John Wiley & Sons: New York, 2007.
[http://dx.doi.org/10.1002/9780470191699]
[5]
Baumann, A.; Lohmann, W.; Schubert, B.; Oberacher, H.; Karst, U. Metabolic studies of tetrazepam based on electrochemical simulation in comparison to in vivo and in vitro methods. J. Chromatogr. A, 2009, 1216(15), 3192-3198.
[http://dx.doi.org/10.1016/j.chroma.2009.02.001] [PMID: 19233363]
[6]
Johansson, T.; Weidolf, L.; Jurva, U. Mimicry of phase I drug metabolism--novel methods for metabolite characterization and synthesis. Rapid Commun. Mass Spectrom., 2007, 21(14), 2323-2331.
[http://dx.doi.org/10.1002/rcm.3077] [PMID: 17575570]
[7]
Holčapek, M.; Kolárová, L.; Nobilis, M. High-performance liquid chromatography-tandem mass spectrometry in the identification and determination of phase I and phase II drug metabolites. Anal. Bioanal. Chem., 2008, 391(1), 59-78.
[http://dx.doi.org/10.1007/s00216-008-1962-7] [PMID: 18345532]
[8]
Lohmann, W.; Karst, U. Simulation of the detoxification of paracetamol using on-line electrochemistry/liquid chromatography/mass spectrometry. Anal. Bioanal. Chem., 2006, 386(6), 1701-1708.
[http://dx.doi.org/10.1007/s00216-006-0801-y] [PMID: 17053920]
[9]
Jurva, U.; Wikström, H.V.; Weidolf, L.; Bruins, A.P. Comparison between electrochemistry/mass spectrometry and cytochrome P450 catalyzed oxidation reactions. Rapid Commun. Mass Spectrom., 2003, 17(8), 800-810.
[http://dx.doi.org/10.1002/rcm.978] [PMID: 12672134]
[10]
Lohmann, W.; Karst, U. Generation and identification of reactive metabolites by electrochemistry and immobilized enzymes coupled on-line to liquid chromatography/mass spectrometry. Anal. Chem., 2007, 79(17), 6831-6839.
[http://dx.doi.org/10.1021/ac071100r] [PMID: 17685550]
[11]
Coleman, M.D. Human drug metabolism; Wiley-Blackwell: Oxford, UK, 2010.
[http://dx.doi.org/10.1002/9780470689332]
[12]
Guengerich, F.P. Intersection of the Roles of Cytochrome P450 enzymes with xenobiotic and endogenous substrates: relevance to toxicity and drug interactions. Chem. Res. Toxicol., 2017, 30(1), 2-12.
[http://dx.doi.org/10.1021/acs.chemrestox.6b00226] [PMID: 27472660]
[13]
Zanger, U.M. In Metabolism of Drugs and Other Xenobiotics; Wiley Online Library: New York, 2012.
[http://dx.doi.org/10.1002/9783527630905.ch10]
[14]
Anzenbacher, P.; Zanger, U.M. Metabolism of drugs and other xenobiotics; John Wiley & Sons: New York, 2012.
[http://dx.doi.org/10.1002/9783527630905]
[15]
Rendic, S.; Guengerich, F.P. Survey of Human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals. Chem. Res. Toxicol., 2015, 28(1), 38-42.
[http://dx.doi.org/10.1021/tx500444e] [PMID: 25485457]
[16]
Guengerich, F.P. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol., 2001, 14(6), 611-650.
[http://dx.doi.org/10.1021/tx0002583] [PMID: 11409933]
[17]
Gad, S.C. Preclinical development handbook: ADME and biopharmaceutical properties; John Wiley & Sons: New York, 2008.
[18]
Bryant, B.; Knights, K. Pharmacology for Health Professionals ebook; Elsevier Health Sciences: Amsterdam, 2014.
[19]
Ioannides, C.; Lewis, D.F. Cytochromes P450 in the bioactivation of chemicals. Curr. Top. Med. Chem., 2004, 4(16), 1767-1788.
[http://dx.doi.org/10.2174/1568026043387188] [PMID: 15579107]
[20]
Oda, S.; Fukami, T.; Yokoi, T.; Nakajima, M. A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab. Pharmacokinet., 2015, 30(1), 30-51.
[http://dx.doi.org/10.1016/j.dmpk.2014.12.001] [PMID: 25760529]
[21]
Evans, W.E.; Johnson, J.A. Pharmacogenomics: The inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet., 2001, 2, 9-39.
[http://dx.doi.org/10.1146/annurev.genom.2.1.9] [PMID: 11701642]
[22]
Zamek-Gliszczynski, M.J.; Hoffmaster, K.A.; Nezasa, K.; Tallman, M.N.; Brouwer, K.L. Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur. J. Pharm. Sci., 2006, 27(5), 447-486.
[http://dx.doi.org/10.1016/j.ejps.2005.12.007] [PMID: 16472997]
[23]
Gamage, N.; Barnett, A.; Hempel, N.; Duggleby, R.G.; Windmill, K.F.; Martin, J.L.; McManus, M.E. Human sulfotransferases and their role in chemical metabolism. Toxicol. Sci., 2006, 90(1), 5-22.
[http://dx.doi.org/10.1093/toxsci/kfj061] [PMID: 16322073]
[24]
Qin, X.; Teesch, L.M.; Duffel, M.W. Modification of the catalytic function of human hydroxysteroid sulfotransferase hSULT2A1 by formation of disulfide bonds. Drug Metab. Dispos., 2013, 41(5), 1094-1103.
[http://dx.doi.org/10.1124/dmd.112.050534] [PMID: 23444386]
[25]
Fura, A.; Shu, Y.Z.; Zhu, M.; Hanson, R.L.; Roongta, V.; Humphreys, W.G. Discovering drugs through biological transformation: Role of pharmacologically active metabolites in drug discovery. J. Med. Chem., 2004, 47(18), 4339-4351.
[http://dx.doi.org/10.1021/jm040066v] [PMID: 15317447]
[26]
Leung, L.; Kalgutkar, A.S.; Obach, R.S. Metabolic activation in drug-induced liver injury. Drug Metab. Rev., 2012, 44(1), 18-33.
[http://dx.doi.org/10.3109/03602532.2011.605791] [PMID: 21939431]
[27]
Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov., 2008, 7(3), 255-270.
[http://dx.doi.org/10.1038/nrd2468] [PMID: 18219308]
[28]
Luffer-Atlas, D.; Atrakchi, A. A decade of drug metabolite safety testing: Industry and regulatory shared learning. Expert Opin. Drug Metab. Toxicol., 2017, 13(9), 897-900.
[http://dx.doi.org/10.1080/17425255.2017.1364362] [PMID: 28797172]
[29]
Tahara, K.; Nishikawa, T.; Hattori, Y.; Iijima, S.; Kouno, Y.; Abe, Y. Production of a reactive metabolite of troglitazone by electrochemical oxidation performed in nonaqueous medium. J. Pharm. Biomed. Anal., 2009, 50(5), 1030-1036.
[http://dx.doi.org/10.1016/j.jpba.2009.06.002] [PMID: 19581066]
[30]
Meyer, U.A. Overview of enzymes of drug metabolism. J. Pharmacokinet. Biopharm., 1996, 24(5), 449-459.
[http://dx.doi.org/10.1007/BF02353473] [PMID: 9131484]
[31]
Pelkonen, O.; Pasanen, M.; Tolonen, A.; Koskinen, M.; Hakkola, J.; Abass, K.; Laine, J.; Hakkinen, M.; Juvonen, R.; Auriola, S.; Storvik, M.; Huuskonen, P.; Rousu, T.; Rahikkala, M. Reactive metabolites in early drug development: Predictive in vitro tools. Curr. Med. Chem., 2015, 22(4), 538-550.
[http://dx.doi.org/10.2174/0929867321666141012175543] [PMID: 25312212]
[32]
Brandon, E.F.; Raap, C.D.; Meijerman, I.; Beijnen, J.H.; Schellens, J.H. An update on in vitro test methods in human hepatic drug biotransformation research: Pros and cons. Toxicol. Appl. Pharmacol., 2003, 189(3), 233-246.
[http://dx.doi.org/10.1016/S0041-008X(03)00128-5] [PMID: 12791308]
[33]
Stalder, R.; Roth, G.P. Preparative microfluidic electrosynthesis of drug metabolites. ACS Med. Chem. Lett., 2013, 4(11), 1119-1123.
[http://dx.doi.org/10.1021/ml400316p] [PMID: 24900614]
[34]
Khera, S.; Hu, N. Generation of statin drug metabolites through electrochemical and enzymatic oxidations. Anal. Bioanal. Chem., 2013, 405(18), 6009-6018.
[http://dx.doi.org/10.1007/s00216-013-7021-z] [PMID: 23760135]
[35]
Kalgutkar, A.S.; Didiuk, M.T. Structural alerts, reactive metabolites, and protein covalent binding: how reliable are these attributes as predictors of drug toxicity? Chem. Biodivers., 2009, 6(11), 2115-2137.
[http://dx.doi.org/10.1002/cbdv.200900055] [PMID: 19937848]
[36]
Hinson, J.A.; Reid, A.B.; McCullough, S.S.; James, L.P. Acetaminophen-induced hepatotoxicity: Role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab. Rev., 2004, 36(3-4), 805-822.
[http://dx.doi.org/10.1081/DMR-200033494] [PMID: 15554248]
[37]
Hinson, J.A.; Roberts, D.W.; James, L.P. Mechanisms of acetaminophen-induced liver necrosis. Handb. Exp. Pharmacol., 2010, (196), 369-405.
[http://dx.doi.org/10.1007/978-3-642-00663-0_12] [PMID: 20020268]
[38]
Pirmohamed, M.; Kitteringham, N.R.; Guenthner, T.M.; Breckenridge, A.M.; Park, B.K. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem. Pharmacol., 1992, 43(8), 1675-1682.
[http://dx.doi.org/10.1016/0006-2952(92)90696-G] [PMID: 1575766]
[39]
Wang, Z.; Smart, R.; Hodgson, E. Molecular and biochemical toxicology; John Wiley & Sons, Inc.: New York, 2007.
[40]
Skipper, P.L.; Kim, M.Y.; Sun, H.L.P.; Wogan, G.N.; Tannenbaum, S.R. Monocyclic aromatic amines as potential human carcinogens: Old is new again. Carcinogenesis, 2010, 31(1), 50-58.
[http://dx.doi.org/10.1093/carcin/bgp267] [PMID: 19887514]
[41]
Büter, L.; Vogel, M.; Karst, U. Adduct formation of electrochemically generated reactive intermediates with biomolecules. TrAC Trend. Anal. Chem., 2015, 70, 74-91.
[http://dx.doi.org/10.1016/j.trac.2015.03.009]
[42]
Srivastava, A.; Maggs, J.L.; Antoine, D.J.; Williams, D.P.; Smith, D.A.; Park, B.K. Role of reactive metabolites in drug-induced hepatotoxicity. Handb. Exp. Pharmacol., 2010, 196, 165-194.
[http://dx.doi.org/10.1007/978-3-642-00663-0_7] [PMID: 20020263]
[43]
Jin, Y.; Regev, A.; Kam, J.; Phipps, K.; Smith, C.; Henck, J.; Campanale, K.; Hu, L.; Hall, D.G.; Yang, X.Y.; Nakano, M.; McNearney, T.A.; Uetrecht, J.; Landschulz, W. Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor. Br. J. Clin. Pharmacol., 2018, 84(1), 179-188.
[http://dx.doi.org/10.1111/bcp.13423] [PMID: 28865237]
[44]
Dalvie, D.; Kang, P.; Zientek, M.; Xiang, C.; Zhou, S.; Obach, R.S. Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. Chem. Res. Toxicol., 2008, 21(12), 2260-2271.
[http://dx.doi.org/10.1021/tx800323w] [PMID: 19548350]
[45]
Zhao, S.X.; Dalvie, D.K.; Kelly, J.M.; Soglia, J.R.; Frederick, K.S.; Smith, E.B.; Obach, R.S.; Kalgutkar, A.S. NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem. Res. Toxicol., 2007, 20(11), 1649-1657.
[http://dx.doi.org/10.1021/tx700132x] [PMID: 17907785]
[46]
Uetrecht, J. Idiosyncratic drug reactions: Past, present, and future. Chem. Res. Toxicol., 2008, 21(1), 84-92.
[http://dx.doi.org/10.1021/tx700186p] [PMID: 18052104]
[47]
Lammert, C.; Bjornsson, E.; Niklasson, A.; Chalasani, N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology, 2010, 51(2), 615-620.
[http://dx.doi.org/10.1002/hep.23317] [PMID: 19839004]
[48]
Stepan, A.F.; Walker, D.P.; Bauman, J.; Price, D.A.; Baillie, T.A.; Kalgutkar, A.S.; Aleo, M.D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: A perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol., 2011, 24(9), 1345-1410.
[http://dx.doi.org/10.1021/tx200168d] [PMID: 21702456]
[49]
Kassahun, K.; Pearson, P.G.; Tang, W.; McIntosh, I.; Leung, K.; Elmore, C.; Dean, D.; Wang, R.; Doss, G.; Baillie, T.A. Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem. Res. Toxicol., 2001, 14(1), 62-70.
[http://dx.doi.org/10.1021/tx000180q] [PMID: 11170509]
[50]
Mitchell, J.R.; Potter, W.Z.; Hinson, J.A.; Jollow, D.J. Hepatic necrosis caused by furosemide. Nature, 1974, 251(5475), 508-511.
[http://dx.doi.org/10.1038/251508a0] [PMID: 4424638]
[51]
You, Q.; Cheng, L.; Reilly, T.P.; Wegmann, D.; Ju, C. Role of neutrophils in a mouse model of halothane-induced liver injury. Hepatology, 2006, 44(6), 1421-1431.
[http://dx.doi.org/10.1002/hep.21425] [PMID: 17133481]
[52]
Park, B.K.; Laverty, H.; Srivastava, A.; Antoine, D.J.; Naisbitt, D.; Williams, D.P. Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity. Chem. Biol. Interact., 2011, 192(1-2), 30-36.
[http://dx.doi.org/10.1016/j.cbi.2010.09.011] [PMID: 20846520]
[53]
Copple, I.M.; Goldring, C.E.; Kitteringham, N.R.; Park, B.K. The keap1-nrf2 cellular defense pathway: mechanisms of regulation and role in protection against drug-induced toxicity. Handb. Exp. Pharmacol., 2010, (196), 233-266.
[http://dx.doi.org/10.1007/978-3-642-00663-0_9] [PMID: 20020265]
[54]
Bisaglia, M.; Soriano, M.E.; Arduini, I.; Mammi, S.; Bubacco, L. Molecular characterization of dopamine-derived quinones reactivity toward NADH and glutathione: implications for mitochondrial dysfunction in Parkinson disease. Biochim. Biophys. Acta, 2010, 1802(9), 699-706.
[http://dx.doi.org/10.1016/j.bbadis.2010.06.006] [PMID: 20600874]
[55]
Muñoz, P.; Huenchuguala, S.; Paris, I.; Segura-Aguilar, J. Dopamine oxidation and autophagy. Parkinsons Dis., 2012, 2012, 920-953.
[http://dx.doi.org/10.1155/2012/920953] [PMID: 22966478]
[56]
Li, Y.; Slatter, J.G.; Zhang, Z.; Li, Y.; Doss, G.A.; Braun, M.P.; Stearns, R.A.; Dean, D.C.; Baillie, T.A.; Tang, W. In vitro metabolic activation of lumiracoxib in rat and human liver preparations. Drug Metab. Dispos., 2008, 36(2), 469-473.
[http://dx.doi.org/10.1124/dmd.107.019018] [PMID: 17998295]
[57]
Liu, J.; Liu, H.; van Breemen, R.B.; Thatcher, G.R.; Bolton, J.L. Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem. Res. Toxicol., 2005, 18(2), 174-182.
[http://dx.doi.org/10.1021/tx0497752] [PMID: 15720121]
[58]
Pearce, R.E.; Lu, W.; Wang, Y.; Uetrecht, J.P.; Correia, M.A.; Leeder, J.S. Pathways of carbamazepine bioactivation in vitro. III. The role of human cytochrome P450 enzymes in the formation of 2,3-dihydroxycarbamazepine. Drug Metab. Dispos., 2008, 36(8), 1637-1649.
[http://dx.doi.org/10.1124/dmd.107.019562] [PMID: 18463198]
[59]
Chen, Q.; Doss, G.A.; Tung, E.C.; Liu, W.; Tang, Y.S.; Braun, M.P.; Didolkar, V.; Strauss, J.R.; Wang, R.W.; Stearns, R.A.; Evans, D.C.; Baillie, T.A.; Tang, W. Evidence for the bioactivation of zomepirac and tolmetin by an oxidative pathway: identification of glutathione adducts in vitro in human liver microsomes and in vivo in rats. Drug Metab. Dispos., 2006, 34(1), 145-151.
[http://dx.doi.org/10.1124/dmd.105.004341] [PMID: 16251255]
[60]
Li, C.; Benet, L.Z.; Grillo, M.P. Studies on the chemical reactivity of 2-phenylpropionic acid 1-O-acyl glucuronide and S-acyl-CoA thioester metabolites. Chem. Res. Toxicol., 2002, 15(10), 1309-1317.
[http://dx.doi.org/10.1021/tx020013l] [PMID: 12387630]
[61]
Cui, D.; Rankin, G.O.; Harvison, P.J. Metabolism of the nephrotoxicant N-(3,5-dichlorophenyl)succinimide in rats: Evidence for bioactivation through alcohol-O-glucuronidation and O-sulfation. Chem. Res. Toxicol., 2005, 18(6), 991-1003.
[http://dx.doi.org/10.1021/tx0496587] [PMID: 15962934]
[62]
Erve, J.C.; Svensson, M.A.; von Euler-Chelpin, H.; Klasson-Wehler, E. Characterization of glutathione conjugates of the remoxipride hydroquinone metabolite NCQ-344 formed in vitro and detection following oxidation by human neutrophils. Chem. Res. Toxicol., 2004, 17(4), 564-571.
[http://dx.doi.org/10.1021/tx034238n] [PMID: 15089099]
[63]
Sun, Q.; Zhu, R.; Foss, F.W., Jr; Macdonald, T.L. In vitro metabolism of a model cyclopropylamine to reactive intermediate: insights into trovafloxacin-induced hepatotoxicity. Chem. Res. Toxicol., 2018, 21(3), 711-719.
[64]
Kadi, A.A. Attwa, Mohamed W.; Darwish, H.W. LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways. RSC Advances, 2018, 8(3), 1182-1190.
[65]
Attwa, M.W.; Kadi, A.A.; Darwish, H.W.; Alrabiah, H. LC-MS/MS reveals the formation of reactive ortho-quinone and iminium intermediates in saracatinib metabolism: Phase I metabolic profiling. Clin. Chim. Acta, 2018, 482, 84-94.
[http://dx.doi.org/10.1016/j.cca.2018.03.037] [PMID: 29614307]
[66]
Godinho, A.L.A.; Martins, I.L.; Nunes, J.; Charneira, C.; Grilo, J.; Silva, D.M.; Pereira, S.A.; Soto, K.; Oliveira, M.C.; Marques, M.M.; Jacob, C.C.; Antunes, A.M.M. High resolution mass spectrometry-based methodologies for identification of Etravirine bioactivation to reactive metabolites: In vitro and in vivo approaches. Eur. J. Pharm. Sci., 2018, 119, 70-82.
[http://dx.doi.org/10.1016/j.ejps.2018.03.026] [PMID: 29592839]
[67]
Shen, F.; Wen, H-M.; Shan, C-X.; Kang, A.; Dong, B.; Chai, C.; Zhang, J-Y.; Zhang, Q.; Li, W. Sulfotransferase-catalyzed biotransformation of liguzinediol and comparison of its metabolism in different species using UFLC-QTOF-MS. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2018, 1089, 1-7.
[http://dx.doi.org/10.1016/j.jchromb.2018.04.048] [PMID: 29738966]
[68]
Johnsi Rani, P.; Vishnuvardhan, C.; Nimbalkar, R.D.; Garg, P.; Satheeshkumar, N. Metabolite characterization of ambrisentan, in in vitro and in vivo matrices by UHPLC/QTOF/MS/MS: Detection of glutathione conjugate of epoxide metabolite evidenced by in vitro GSH trapping assay. J. Pharm. Biomed. Anal., 2018, 155, 320-328.
[http://dx.doi.org/10.1016/j.jpba.2018.04.013] [PMID: 29684813]
[69]
Yang, A-H.; Zhang, L.; Zhi, D-X.; Liu, W-L.; Gao, X.; He, X. Identification and analysis of the reactive metabolites related to the hepatotoxicity of safrole. Xenobiotica, 2018, 48(11), 1164-1172.
[http://dx.doi.org/10.1080/00498254.2017.1399227] [PMID: 29082813]
[70]
Amer, S.M.; Kadi, A.A.; Darwish, H.W.; Attwa, M.W. Identification and characterization of in vitro phase I and reactive metabolites of masitinib using a LC-MS/MS method: Bioactivation pathway elucidation. RSC Advances, 2017, 7(8), 4479-4491.
[http://dx.doi.org/10.1039/C6RA25767D]
[71]
Orhan, H.; Vermeulen, N.P. Conventional and novel approaches in generating and characterization of reactive intermediates from drugs/drug candidates. Curr. Drug Metab., 2011, 12(4), 383-394.
[http://dx.doi.org/10.2174/138920011795202974] [PMID: 21395525]
[72]
Lohmann, W.; Karst, U. Biomimetic modeling of oxidative drug metabolism: Strategies, advantages and limitations. Anal. Bioanal. Chem., 2008, 391(1), 79-96.
[http://dx.doi.org/10.1007/s00216-007-1794-x] [PMID: 18163163]
[73]
Cusack, K.P.; Koolman, H.F.; Lange, U.E.W.; Peltier, H.M.; Piel, I.; Vasudevan, A. Emerging technologies for metabolite generation and structural diversification. Bioorg. Med. Chem. Lett., 2013, 23(20), 5471-5483.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.003] [PMID: 23992859]
[74]
Lohmann, W.; Karst, U. Electrochemistry meets enzymes: Instrumental on-line simulation of oxidative and conjugative metabolism reactions of toremifene. Anal. Bioanal. Chem., 2009, 394(5), 1341-1348.
[http://dx.doi.org/10.1007/s00216-008-2586-7] [PMID: 19139854]
[75]
Schmid, R.D.; Urlacher, V. Modern biooxidation: Enzymes, reactions and applications; John Wiley & Sons: Ney York, 2007.
[http://dx.doi.org/10.1002/9783527611522]
[76]
Testa, B.; Krämer, S.D. The biochemistry of drug metabolism--an introduction: Part 4. reactions of conjugation and their enzymes. Chem. Biodivers., 2008, 5(11), 2171-2336.
[http://dx.doi.org/10.1002/cbdv.200890199] [PMID: 19035562]
[77]
Venisetty, R.K.; Ciddi, V. Application of microbial biotransformation for the new drug discovery using natural drugs as substrates. Curr. Pharm. Biotechnol., 2003, 4(3), 153-167.
[http://dx.doi.org/10.2174/1389201033489847] [PMID: 12769760]
[78]
Arisawa, A.; Agematu, H. A modular approach to biotransformation using microbial cytochrome P450 monooxygenases. Modern Biooxid.: Enzym. React. Appl., 2007, 2007, 177-192.
[79]
Reinen, J.; van Leeuwen, J.S.; Li, Y.; Sun, L.; Grootenhuis, P.D.J.; Decker, C.J.; Saunders, J.; Vermeulen, N.P.E.; Commandeur, J.N.M. Efficient screening of cytochrome P450 BM3 mutants for their metabolic activity and diversity toward a wide set of drug-like molecules in chemical space. Drug Metab. Dispos., 2011, 39(9), 1568-1576.
[http://dx.doi.org/10.1124/dmd.111.039461] [PMID: 21673132]
[80]
Li, W.; Josephs, J.L.; Skiles, G.L.; Humphreys, W.G. Metabolite generation via microbial biotransformations with actinomycetes: Rapid screening for active strains and biosynthesis of important human metabolites of two development-stage compounds, 5-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101) and Dasatinib. Drug Metab. Dispos., 2008, 36(4), 721.
[http://dx.doi.org/10.1124/dmd.107.019570] [PMID: 18227141]
[81]
Fischer, V.; Johanson, L.; Heitz, F.; Tullman, R.; Graham, E.; Baldeck, J-P.; Robinson, W.T. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: Effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab. Dispos., 1999, 27(3), 410-416.
[PMID: 10064574]
[82]
Novik, E.; Maguire, T.J.; Chao, P.; Cheng, K.C.; Yarmush, M.L. A microfluidic hepatic coculture platform for cell-based drug metabolism studies. Biochem. Pharmacol., 2010, 79(7), 1036-1044.
[http://dx.doi.org/10.1016/j.bcp.2009.11.010] [PMID: 19925779]
[83]
Kuhl, N.; Hopkinson, M.N.; Wencel-Delord, J.; Glorius, F. Beyond directing groups: Transition-metal-catalyzed C-H activation of simple arenes. Angew. Chem. Int. Ed. Engl., 2012, 51(41), 10236-10254.
[http://dx.doi.org/10.1002/anie.201203269] [PMID: 22996679]
[84]
Zhang, K.E.; Wu, E.; Patick, A.K.; Kerr, B.; Zorbas, M.; Lankford, A.; Kobayashi, T.; Maeda, Y.; Shetty, B.; Webber, S. Circulating metabolites of the human immunodeficiency virus protease inhibitor nelfinavir in humans: structural identification, levels in plasma, and antiviral activities. Antimicrob. Agents Chemother., 2001, 45(4), 1086-1093.
[http://dx.doi.org/10.1128/AAC.45.4.1086-1093.2001] [PMID: 11257019]
[85]
Gómez, L.; Canta, M.; Font, D.; Prat, I.; Ribas, X.; Costas, M. Regioselective oxidation of nonactivated alkyl C-H groups using highly structured non-heme iron catalysts. J. Org. Chem., 2013, 78(4), 1421-1433.
[http://dx.doi.org/10.1021/jo302196q] [PMID: 23301685]
[86]
Ma, S.; Subramanian, R. Detecting and characterizing reactive metabolites by liquid chromatography/tandem mass spectrometry. J. Mass Spectrom., 2006, 41(9), 1121-1139.
[http://dx.doi.org/10.1002/jms.1098] [PMID: 16967439]
[87]
Álvarez-Lueje, A.; Pérez, M.; Zapata, C. Electrochemical methods for the in vitro assessment of drug metabolism; Topics on Drug Metabolism, InTech: London, 2012.
[http://dx.doi.org/10.5772/28647]
[88]
Evans, D.C.; Watt, A.P.; Nicoll-Griffith, D.A.; Baillie, T.A. Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol., 2004, 17(1), 3-16.
[http://dx.doi.org/10.1021/tx034170b] [PMID: 14727914]
[89]
Takakusa, H.; Masumoto, H.; Yukinaga, H.; Makino, C.; Nakayama, S.; Okazaki, O.; Sudo, K. Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab. Dispos., 2008, 36(9), 1770-1779.
[http://dx.doi.org/10.1124/dmd.108.021725] [PMID: 18508880]
[90]
Obach, R.S.; Kalgutkar, A.S.; Soglia, J.R.; Zhao, S.X. Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem. Res. Toxicol., 2008, 21(9), 1814-1822.
[http://dx.doi.org/10.1021/tx800161s] [PMID: 18690722]
[91]
Usui, T.; Mise, M.; Hashizume, T.; Yabuki, M.; Komuro, S. Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. Drug Metab. Dispos., 2009, 37(12), 2383-2392.
[http://dx.doi.org/10.1124/dmd.109.028860] [PMID: 19720731]
[92]
Nakayama, S.; Atsumi, R.; Takakusa, H.; Kobayashi, Y.; Kurihara, A.; Nagai, Y.; Nakai, D.; Okazaki, O. A zone classification system for risk assessment of idiosyncratic drug toxicity using daily dose and covalent binding. Drug Metab. Dispos., 2009, 37(9), 1970-1977.
[http://dx.doi.org/10.1124/dmd.109.027797] [PMID: 19487250]
[93]
Thompson, R.A.; Isin, E.M.; Li, Y.; Weidolf, L.; Page, K.; Wilson, I.; Swallow, S.; Middleton, B.; Stahl, S.; Foster, A.J.; Dolgos, H.; Weaver, R.; Kenna, J.G. In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem. Res. Toxicol., 2012, 25(8), 1616-1632.
[http://dx.doi.org/10.1021/tx300091x] [PMID: 22646477]
[94]
Gan, J.; Harper, T.W.; Hsueh, M.M.; Qu, Q.; Humphreys, W.G. Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem. Res. Toxicol., 2005, 18(5), 896-903.
[http://dx.doi.org/10.1021/tx0496791] [PMID: 15892584]
[95]
Takakusa, H.; Masumoto, H.; Makino, C.; Okazaki, O.; Sudo, K. Quantitative assessment of reactive metabolite formation using 35S-labeled glutathione. Drug Metab. Pharmacokinet., 2009, 24(1), 100-107.
[http://dx.doi.org/10.2133/dmpk.24.100] [PMID: 19252339]
[96]
Yan, Z.; Caldwell, G.W. Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal. Chem., 2004, 76(23), 6835-6847.
[http://dx.doi.org/10.1021/ac040159k] [PMID: 15571331]
[97]
Soglia, J.R.; Contillo, L.G.; Kalgutkar, A.S.; Zhao, S.; Hop, C.E.; Boyd, J.G.; Cole, M.J. A semiquantitative method for the determination of reactive metabolite conjugate levels in vitro utilizing liquid chromatography-tandem mass spectrometry and novel quaternary ammonium glutathione analogues. Chem. Res. Toxicol., 2006, 19(3), 480-490.
[http://dx.doi.org/10.1021/tx050303c] [PMID: 16544956]
[98]
Hartman, N.R.; Cysyk, R.L.; Bruneau-Wack, C.; Thénot, J.P.; Parker, R.J.; Strong, J.M. Production of intracellular 35S-glutathione by rat and human hepatocytes for the quantification of xenobiotic reactive intermediates. Chem. Biol. Interact., 2002, 142(1-2), 43-55.
[http://dx.doi.org/10.1016/S0009-2797(02)00053-4] [PMID: 12399154]
[99]
Wen, B.; Fitch, W.L. Screening and characterization of reactive metabolites using glutathione ethyl ester in combination with Q-trap mass spectrometry. J. Mass Spectrom., 2009, 44(1), 90-100.
[http://dx.doi.org/10.1002/jms.1475] [PMID: 18720456]
[100]
Yan, Z.; Maher, N.; Torres, R.; Caldwell, G.W.; Huebert, N. Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry. Rapid Commun. Mass Spectrom., 2005, 19(22), 3322-3330.
[http://dx.doi.org/10.1002/rcm.2195] [PMID: 16235238]
[101]
Zhang, C.; Wong, S.; Delarosa, E.M.; Kenny, J.R.; Halladay, J.S.; Hop, C.E.; Khojasteh-Bakht, S.C. Inhibitory properties of trapping agents: Glutathione, potassium cyanide, and methoxylamine, against major human cytochrome p450 isoforms. Drug Metab. Lett., 2009, 3(2), 125-129.
[http://dx.doi.org/10.2174/187231209788654126] [PMID: 19601875]
[102]
Shebley, M.; Jushchyshyn, M.I.; Hollenberg, P.F. Selective pathways for the metabolism of phencyclidine by cytochrome p450 2b enzymes: identification of electrophilic metabolites, glutathione, and N-acetyl cysteine adducts. Drug Metab. Dispos., 2006, 34(3), 375-383.
[http://dx.doi.org/10.1124/dmd.105.007047] [PMID: 16326815]
[103]
Prakash, C.; Sharma, R.; Gleave, M.; Nedderman, A. In vitro screening techniques for reactive metabolites for minimizing bioactivation potential in drug discovery. Curr. Drug Metab., 2008, 9(9), 952-964.
[http://dx.doi.org/10.2174/138920008786485209] [PMID: 18991592]
[104]
Kennedy, K.A.; Sligar, S.G.; Polomski, L.; Sartorelli, A.C. Metabolic activation of mitomycin C by liver microsomes and nuclei. Biochem. Pharmacol., 1982, 31(11), 2011-2016.
[http://dx.doi.org/10.1016/0006-2952(82)90414-2] [PMID: 6810899]
[105]
Jurva, J.U. Electrochemistry on-line with mass spectrometry: Instrumental methods for in vitro generation and detection of drug metabolites; Groningen: Netherlands. , 2004.
[106]
Baumann, A.; Pfeifer, T.; Melles, D.; Karst, U. Investigation of the biotransformation of melarsoprol by electrochemistry coupled to complementary LC/ESI-MS and LC/ICP-MS analysis. Anal. Bioanal. Chem., 2013, 405(15), 5249-5258.
[http://dx.doi.org/10.1007/s00216-013-6929-7] [PMID: 23552974]
[107]
Karady, M.; Novák, O.; Horna, A.; Strnad, M.; Doležal, K. High performance liquid chromatography‐electrochemistry‐electrospray ionization mass spectrometry (HPLC/EC/ESI‐MS) for detection and characterization of roscovitine oxidation products. Electroanalysis, 2011, 23(12), 2898-2905.
[http://dx.doi.org/10.1002/elan.201100383]
[108]
Odijk, M.; Baumann, A.; Olthuis, W.; van den Berg, A.; Karst, U. Electrochemistry-on-chip for on-line conversions in drug metabolism studies. Biosens. Bioelectron., 2010, 26(4), 1521-1527.
[http://dx.doi.org/10.1016/j.bios.2010.07.102] [PMID: 20728333]
[109]
van den Brink, F.T.G.; Büter, L.; Odijk, M.; Olthuis, W.; Karst, U.; van den Berg, A. Mass spectrometric detection of short-lived drug metabolites generated in an electrochemical microfluidic chip. Anal. Chem., 2015, 87(3), 1527-1535.
[http://dx.doi.org/10.1021/ac503384e] [PMID: 25531627]
[110]
Anzenbacher, P.; Zanger, U.M. Metabolism of drugs and other xenobiotics; John Wiley & Sons: New York, 2012.
[http://dx.doi.org/10.1002/9783527630905]
[111]
Bussy, U.; Chung-Davidson, Y.W.; Li, K.; Li, W. Phase I and phase II reductive metabolism simulation of nitro aromatic xenobiotics with electrochemistry coupled with high resolution mass spectrometry. Anal. Bioanal. Chem., 2014, 406(28), 7253-7260.
[http://dx.doi.org/10.1007/s00216-014-8171-3] [PMID: 25234306]
[112]
Yoshioka, K.; Kato, D.; Kamata, T.; Niwa, O. Cytochrome P450 modified polycrystalline indium tin oxide film as a drug metabolizing electrochemical biosensor with a simple configuration. Anal. Chem., 2013, 85(21), 9996-9999.
[http://dx.doi.org/10.1021/ac402661w] [PMID: 24117377]
[113]
Nouri-Nigjeh, E.; Permentier, H.P.; Bischoff, R.; Bruins, A.P. Electrochemical oxidation by square-wave potential pulses in the imitation of oxidative drug metabolism. Anal. Chem., 2011, 83(14), 5519-5525.
[http://dx.doi.org/10.1021/ac200897p] [PMID: 21644593]

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